The clinician and the mode of action of ECT Yiannis G. Papakostas, MD Associate Professor of Psychiatry March,12, 2005 March,12, 2005.

The clinician and the mode of action of ECT

Yiannis G. Papakostas, MDYiannis G. Papakostas, MD

Associate Professor of PsychiatryAssociate Professor of Psychiatry

March,12, 2005March,12, 2005

There are several reasons that make the There are several reasons that make the issue of the mode of ECT action issue of the mode of ECT action important and relevant to the clinicians important and relevant to the clinicians who recommend or use this treatment who recommend or use this treatment in their every day practice in their every day practice

First, the clinician will be able to First, the clinician will be able to dispute the unfounded claims that dispute the unfounded claims that ECT still remains an empirical ECT still remains an empirical treatment with its mechanism of treatment with its mechanism of action not amenable to scientific action not amenable to scientific explorationexploration

Next, a clinician aware of the main Next, a clinician aware of the main findings regarding ECT’s action is findings regarding ECT’s action is in a better position to apply this in a better position to apply this treatment in an optimal manner in treatment in an optimal manner in order to maximize its benefits and order to maximize its benefits and minimize its side-effects minimize its side-effects

Lastly, update knowledge regarding the Lastly, update knowledge regarding the mode of ECT action enables the mode of ECT action enables the clinician to foresee future clinician to foresee future developments that will hopefully developments that will hopefully further improve ECT’s clinical further improve ECT’s clinical applicability and status applicability and status

Difficulties in investigating the mechanisms of ECT action

ECT involves so many changes that the ECT involves so many changes that the difficulty lies not in demonstrating difficulty lies not in demonstrating such changes, but in differentiating such changes, but in differentiating which of the changes may be related to which of the changes may be related to the antidepressive effect and which are the antidepressive effect and which are quite irrelevant to itquite irrelevant to it

Mechanisms of ECT actionThe “Brain damage” claim

There are those who argue that There are those who argue that ECT is brain –damaging or ECT is brain –damaging or

brain-disablingbrain-disabling

No evidence for such a claim..

Under routine ECT practice, Under routine ECT practice, mostmost of the of the cognitive changescognitive changes are transient are transient

Human post-mortem studies Human post-mortem studies have not have not linked linked neuronal loss to ECT neuronal loss to ECT

Prospective structural Prospective structural brain brain imaging studies imaging studies have not have not observed observed any ECT changesany ECT changes

Therefore..

«Not only hasn’t the brain damage theory «Not only hasn’t the brain damage theory been proven, it has been disproven»been proven, it has been disproven»

Harold SackeimHarold Sackeim

Theories of mechanisms of ECT action

A.A. Neuropsychological Neuropsychological B.B. NeurophysiologicalNeurophysiologicalC.C. Neuroendocrinological Neuroendocrinological D.D. Neurobiochemical Neurobiochemical E.E. Post-receptor theoriesPost-receptor theories

A. Neuropsychological theories

Therapeutic Therapeutic ingredient ingredient

Evidence against Evidence against

Negative emotions Negative emotions (Fear, punishment, (Fear, punishment, “pain”) induced by “pain”) induced by ECT ECT

Modified ECT (anaesthesia, muscle relaxation, (anaesthesia, muscle relaxation, oxygenation) eliminates the traumatic and oxygenation) eliminates the traumatic and fearful aspects but not the therapeutic effect fearful aspects but not the therapeutic effect

OBS (confusion, retrograde amnesia, anosoagnosia, denial of illness)

No correlation between memory disturbance No correlation between memory disturbance and ECT’s therapeutic benefitand ECT’s therapeutic benefit

UECT is therapeutic with little demonstrated is therapeutic with little demonstrated loss of memory. loss of memory.

Placebo effect In double-blind trials real ECT was more double-blind trials real ECT was more effective than simulated (SHAM) ECT effective than simulated (SHAM) ECT

B. Neurophysiological theories

Generalized seizureGeneralized seizureECT as an anti-convulsant ECT as an anti-convulsant

The role of generalized seizure

necessarynecessary but not sufficientbut not sufficient

Sub-convulsive stimulation Sub-convulsive stimulation is ineffectiveis ineffectiveBlocking full expression Blocking full expression with lidocaine undermines with lidocaine undermines efficacyefficacyChemical convulsants are Chemical convulsants are effectiveeffective

Generalized seizures can be Generalized seizures can be produced that lack produced that lack antidepressant propertiesantidepressant properties

Anticonvulsant properties of ECT:

Increases in seizure threshold over the treatment courseIncreases in seizure threshold over the treatment course Decrease in seizure duration over the treatment courseDecrease in seizure duration over the treatment course Ictal and postictal findings from EEG, cerebral blood flow Ictal and postictal findings from EEG, cerebral blood flow

and metabolic rate for glucose are indicative of and metabolic rate for glucose are indicative of inhibitory(anticonvulsant) processes. inhibitory(anticonvulsant) processes.

Enhanced transmission of inhibitory neurotransmitters Enhanced transmission of inhibitory neurotransmitters (GABA) and neuropeptides (opiods, TRH)(GABA) and neuropeptides (opiods, TRH)

ECT has an anticonvulsant effect in intractable seizure ECT has an anticonvulsant effect in intractable seizure disorders and status epilepticus in humansdisorders and status epilepticus in humans

Anticonvulsant effects in animal models of epilepsy

CSF taken from post ECS animal and CSF taken from post ECS animal and injected into the ventricular system of a injected into the ventricular system of a naïve animal results in an increase in naïve animal results in an increase in seizure threshold seizure threshold

Furthermore, this transfer of an Furthermore, this transfer of an anticonvulsant effect can be blocked by pre-anticonvulsant effect can be blocked by pre-treatment with naloxone treatment with naloxone

Clinical evidence supporting the anticonvulsant hypothesis of ECT

The magnitude of the seizure threshold The magnitude of the seizure threshold increase is linked to the clinical responseincrease is linked to the clinical response

Right unilateral ECT that is therapeutically Right unilateral ECT that is therapeutically weaker than bilateral ECT elevates weaker than bilateral ECT elevates threshold to a considerably lower extent threshold to a considerably lower extent than bilateral ECT than bilateral ECT

Evidence against the anticonvulsant theory

Antideperssants do not raise the seizure Antideperssants do not raise the seizure thresholdthreshold

Anticonvulsants like benzodiazepines Anticonvulsants like benzodiazepines are not effective are not effective

C. Neuroendocrine (diencephalic) theories

ECT is particularly effective for these ECT is particularly effective for these depressive symptoms that are indicative of depressive symptoms that are indicative of disturbances in and around hypothalamus disturbances in and around hypothalamus

BECT that is more effective than UECT BECT that is more effective than UECT results in greater global diencephalic results in greater global diencephalic activationactivation

Primary tool of testing these theories: Prolactin secretion because

The rapid, robust and transient increase in The rapid, robust and transient increase in plasma prolactin (PRL) immediately after plasma prolactin (PRL) immediately after ECT is by far the most consistent ECT is by far the most consistent neurochemical result of ECT-induced neurochemical result of ECT-induced seizures seizures

Seizure-associated PRL secretion occurs duringSeizure-associated PRL secretion occurs during ECSECS ECTECT Drug-induced seizuresDrug-induced seizures Spontaneous seizures (epilepsy)Spontaneous seizures (epilepsy)

but not duringbut not during Transcranial magnetic stimulation (TMS)Transcranial magnetic stimulation (TMS)

PRL-secretion and ECT effect may be PRL-secretion and ECT effect may be linked because the are both higher with linked because the are both higher with

bilateral (BECT) as opposed to unilateral ECT bilateral (BECT) as opposed to unilateral ECT (UECT)(UECT)

sinocidal as opposed to brief pulse ECTsinocidal as opposed to brief pulse ECT

However…

Despite these findings, definite conclusions Despite these findings, definite conclusions regarding both, the mechanisms of PRL regarding both, the mechanisms of PRL release during ECT release during ECT (PRL as a research (PRL as a research tool)tool) and its correlation with the treatment and its correlation with the treatment outcome outcome (PRL as therapeutic monitoring (PRL as therapeutic monitoring tool)tool) cannot be drawn at the moment cannot be drawn at the moment

HPT AXIS and

ECSECS Rat brain concentrations Rat brain concentrations

of TRH are increased of TRH are increased after ECSafter ECS

ECTECT Increases plasma TSH Increases plasma TSH Addition of Addition of

triiodothyronine (T3) to triiodothyronine (T3) to ECT enhances the ECT enhances the antidepressant response antidepressant response and reduces cognitive and reduces cognitive adverse effectsadverse effects

Hypothalamic-pituitary-adrenal (HPA) axis and ECT

ECT acutely enhances ECT acutely enhances HPA axis activity HPA axis activity

Successful treatment Successful treatment with ECT is associated with ECT is associated with a decrease with a decrease activity of the APA activity of the APA axisaxis

D. Neurochemical theories

Noradrenaline (NE)Noradrenaline (NE) Serotonin (5-HT)Serotonin (5-HT) Dopamine (DA)Dopamine (DA) Acetylocholine (Ach)Acetylocholine (Ach) Gamma- aminobutyric acid (GABA)Gamma- aminobutyric acid (GABA)

Noradrenergic (NE) neurotransmission and

ECSECS ECS ECS ––like like

antidepressants- antidepressants- causes down causes down regulation of the beta-regulation of the beta-adrenergic receptors adrenergic receptors after one week of after one week of treatment and remains treatment and remains so after one week of so after one week of treatment terminationtreatment termination

ECTECT Transient plasma NE Transient plasma NE

increases in each ECT increases in each ECT session session

These transient These transient changes may be more changes may be more relevant to ECT relevant to ECT effects on cardiac effects on cardiac function than to the function than to the efficacy. efficacy.

Serotonergic(5-HT) neurotransmission and

ECSECS Repeated ECS Repeated ECS

increases the density increases the density of 5-HT2 receptors, as of 5-HT2 receptors, as opposed to 5-HT2 opposed to 5-HT2 receptor down receptor down regulation obtained regulation obtained with antidepressants with antidepressants

ECTECT A course of ECT A course of ECT

increases CSF HIAA increases CSF HIAA levels, which is levels, which is opposite to the effect opposite to the effect of chronic of chronic administration of administration of antidepressantsantidepressants

Dopaminergic (DA) neurotransmission and

ECSECS Significant increase in Significant increase in

DA levels in the DA levels in the striatum after ECSstriatum after ECS

ECTECT Increases the Increases the

concentration of concentration of homovanillic acid homovanillic acid (HVA) in CSF(HVA) in CSF

It has an antipsychotic, It has an antipsychotic, and- as opposed to and- as opposed to neuroleptics - an neuroleptics - an antiparkinsonian effectantiparkinsonian effect

Cholinergic neurotransmission and

ECSECS small reduction in small reduction in

cholinergic cholinergic neurotransmissionneurotransmission

ECTECT Reduction in Reduction in

cholinergic function cholinergic function that may be relevant to that may be relevant to the cognitive side the cognitive side effects of ECTeffects of ECT

Glutaminergic (GABA) neurotransmission and

DepressionDepression

Some -but not all- studies have reported Some -but not all- studies have reported plasma, CSF and occipital GABA levels plasma, CSF and occipital GABA levels decreased in depression decreased in depression

Glutaminergic (GABA) neurotransmission and

ECSECS Up regulation of Up regulation of

GABA receptors after GABA receptors after a course of ECSa course of ECS

ECTECT Increases occipital Increases occipital

cortex GABA cortex GABA GABA increase may GABA increase may

contribute to both the contribute to both the anti-convulsant and anti-convulsant and anti-depressant actions anti-depressant actions of ECTof ECT

E. Post-receptor theories of ECT action

ECT increases the concentrations of the intracellular ECT increases the concentrations of the intracellular second messenger cAMPsecond messenger cAMP in the hippocampus and in the hippocampus and cerebral cortex cerebral cortex

These increased concentrations in turn trigger other These increased concentrations in turn trigger other processes processes [[such as an increase in protein kinase such as an increase in protein kinase activity, increased gene expressionactivity, increased gene expression etc] etc], and , and ultimately upregulation of the ultimately upregulation of the

Brain -derived neurotrophic factor (BDNF)Brain -derived neurotrophic factor (BDNF)

BDNF has been shown to increase synaptic BDNF has been shown to increase synaptic strengthstrength,,survivalsurvival, and , and growthgrowth of a of adult dult neurons, neurons, aand sprouting of serotonergic terminals nd sprouting of serotonergic terminals

ECT may reverse the atrophy of stress-vulnerable ECT may reverse the atrophy of stress-vulnerable neurons or protects them from any further damage neurons or protects them from any further damage by regulation of these neurotrophic factorsby regulation of these neurotrophic factors

Concluding remarks

In spite of the remarkable progress that we have In spite of the remarkable progress that we have witnessed the last two decades concerning the witnessed the last two decades concerning the mechanism of ECT actionmechanism of ECT action

“ “ No hypothesis for the mode of action of any No hypothesis for the mode of action of any

psychiatric treatment- be it electroshock, psychiatric treatment- be it electroshock, psychotropic medicines or the “talk” psychotropic medicines or the “talk” psychotherapies- is satisfactory”psychotherapies- is satisfactory”

Max Fink (2000) American ScientistMax Fink (2000) American Scientist